1. Field of the Invention
The present invention relates to methods of increasing cytidine levels by administering an exogenous uridine source and in particular to the pharmacological use of said uridine or uridine source alone or in combination with other pharmaceutical substances in treating certain neurological disorders.
2. Description of the Related Art
This invention stems from unexpected discovery that increase in levels of uridine following the administration of uridine or uridine source to certain animals comprising human patients, leads to increased levels of cytidine in a human body and particularly in the human brain. Thus, administering uridine or uridine precursors to human patients in need thereof can be as beneficial as administration of cytidine or cytidine precursors. However, the potential benefit of uridine or uridine source administration is overwhelmingly greater than the benefit of cytidine administration. This is due to the fact that cytidine, as opposed to uridine, either cannot cross or is much less efficient than uridine in crossing the blood-brain barrier (Cornford et al., Independent blood-brain barrier transport systems for nucleic acid precursors. Biochim. Biophys. Acta 349:211-219, 1975).
According to the knowledge relating to the metabolism of pyrimidine compounds, enzymes are known in the art, such as cytidine deaminase (EC 3.5.4.5), which converts cytidine into uridine. Cytidine deaminase can be found in some prokaryotes and eukaryotes including humans, primates, and some rodents although some species lack this enzyme. However, according to EC (enzyme classification) list there are no known examples of aminase-like enzymes, which are capable of opposite action, i.e., converting uridine into cytidine.
The prior art relating to the process of uridine to cytidine conversion is also limited. Only one publication, citing two earlier references, seems to exist, wherein it was suggested that a soluble fraction of the rat liver and possibly of the brain may catalyze in vitro and in vivo the conversion of uridine nucleotide to cytidine nucleotide (Dawson. Enzymic conversion of uridine nucleotide to cytidine precursor by rat brain. J. Neurochem. 15:31-34, 1968). Even though this report implicated the possibility of such an enzyme reaction in rats the activity of the enzyme does not appear to be sufficiently potent. As compared to the initial, administered dose of uridine (considered as 100%), the highest levels of newly converted cytidine in vivo were 12.4% in the liver and 9% in the brain. The conversion rates in vitro were 5.4% in the liver and 8.05% in the brain. Thus, maximum observed levels were within 5.4-12.4% range. From a statistical point of view all these figures are within the range of a typical scatter in a gamma counter (15%) and practitioner in the art can dismiss them either as insignificant or irreproducible. Moreover, Dawson himself states that he was unable to recover a nucleotide with spectrophotometric characteristics of cytidine and admits that his conclusions were based on probabilistic guessing. Thus, the alleged phenomenon observed by Dawson may have been due to misinterpretation of an experimental artifact as it is now known that experimentally measurable cytidine can be easily confused with tyrosine, which is chemically unrelated amino acid compound (see FIG. 1).
Thus, even though an enzyme catalyzing the conversion of uridine to cytidine may exist in rats its activity is not sufficiently potent to raise the levels of cytidine to a level that can be measured and ascertained beyond any doubt. Thus, these levels may be not sufficient to warrant practical exploitation for clinical application. Indeed nowhere in Dawson publication is there a suggestion or an attempt to make a suggestion that the uridine to cytidine conversion process can be useful for any medical modality. In addition, as it is the case with many other enzymes and metabolic pathways, this particular enzyme may have been present in rats but not in humans. One skilled in related art knows that a discovery of a biological process in one species of an animal, e.g., rat, does not necessarily means that a similar process is present in another animal, e.g., man. Based on that one skilled in the art will be not sufficiently motivated to exploit this phenomenon for any useful purposes other than an experimental tool to study enzyme metabolism in rats. Consequently, the prior art is silent in regard to the use of the process of uridine to cytidine conversion for any meaningful application.
Uridine is a pyrimidine nucleoside and is essential in the synthesis of ribonucleic acids and tissue glycogens such as UDP glucose and UTP glucose. Medical uses of uridine alone are limited to treatment of genetic disorders related to deficiencies of pyrimidine synthesis such as orotic aciduria (Becroft D M, et al., Hereditary orotic aciduria: long-term therapy with uridine and a trial of uracil. J Pediatr. 1969 November; 75(5): 885-891). Other less common uses of uridine alone are known such as treatment of seizures and epilepsy (Roberts C A, et al., Uridine anticonvulsant effects: selective control of nucleoside incorporation in experimental epilepsy. Epilepsia. 1974 December; 15(4): 479-500). Most commonly, uridine is used in combination with cytidine (Monticone G F, et al., On the therapeutic use of the nucleosides, cytidine and uridine, in some neurological diseases. Minerva Med. 1966 Dec. 19; 57(101): 4348-4352). The uses of this particular dual combination range from liver and kidney diseases to a number of neurological and cerebrovascular diseases but such uses are irrelevant to the present invention directed at the use of uridine without concomitant use with cytidine.
U.S. Pat. No. 4,960,759, issued to De Luca et al., on Oct. 2, 1990 discloses the pharmacological use of uridine in the treatment of nervous disorders such as schizophrenia and Parkinson's disease. De Luca et al., teach that the benefit of uridine is due to increase in cholecystokinin levels in the brain, which in turn improves dopamine functioning and results in therapeutic benefit. Said benefit is described as a reduction in symptoms of Parkinson's disease, which are tremor and rigidity. As the preferred embodiment of the instant invention is treatment of neurological disorders unrelated to schizophrenia and Parkinson's disease it is clear that the teachings by De Luca et al., are irrelevant to this invention.
The U.S. Pat. No. 5,470,838, issued to von Borstel et al., on Nov. 28, 1995 discloses the method of delivering exogenous uridine or cytidine in form of acylated uridine or cytidine and said compounds as useful in treating cardiac insufficiency, myocardial infarction, and cirrhosis of the liver. Von Borstel et al., propose to use both forms of pyrimidines since it was not obvious to them that uridine alone is effective. The absolute requirement of both cytidine and uridine was due to the lack of knowledge and anticipation in the prior art that uridine might convert into cytidine, especially in humans. One skilled in the art will recognize that the disclosed composition matter is different and diseases to be treated are not the same as in the present invention.
The U.S. Pat. Nos. 5,141,943; 5,567,689; and 5,723,449 disclose various methods and compositions to raise levels of uridine in the blood as useful for reducing toxicity of pyrimidine nucleoside drugs such as AZT and 5-Fluouracil for AIDS and cancer therapy respectively. It is apparent to anyone skilled in the art that these teachings have nothing in common with the present invention.
Although all of these patents and prior art references disclose at least one or another aspect of the instant invention none of them taught specifically that cytidine levels can be raised in humans by administering uridine or uridine source as useful for the treatment of certain neurological or brain disorders. These disorders comprise disorders associated with aging such as memory decline and age related decline in cognition functions. These disorders also comprise memory decline and related cognition dysfunction associated with pathological conditions like Alzheimer's disease, Pick's disease, Lewy Body disease, and/or dementias like Huntington's disease and AIDS dementia. Other cognitive dysfunctions, i.e., disorders of attention, alertness, concentration, focus, and dyslexia can also be treated. Other uses of uridine therapy can be imagined such as treatment of mood and emotional disorders, e.g., mania, depression, stress, panic, anxiety, insomnia, dysthemia, psychosis, seasonal effective disorders and bipolar disorders. Neurological diseases like ataxias, including Friedreich's ataxia and movement disorders like tardive dyskinesia can also be treated. Method of treating stroke, cerebral thrombosis, ischemia, and related cerebrovascular diseases resulting from hypoxia as well as behavioral and neurological syndromes seen after brain trauma, spinal cord injury and/or anoxia can be also imagined. Methods of treating diseases of the peripheral nervous system, e.g., neuromuscular disorders like myasthenia gravis, the post-polio syndrome, and muscular dystrophies are also possible. It is also possible to imagine the methods of treating neurological diseases associated with dopaminergic pathway, e.g., schizophrenia and Parkinson's disease as treated by combination therapy in which uridine is one of constituents.
Thus, none of the prior art patents or references have anticipated or made the instant invention obvious. The present invention is thus unique and stands out in the light of the prior art.